Agency Response Letter GRAS Notice No. GRN 000410
CFSAN/Office of Food Additive Safety
March 26, 2012
James T. Heimbach, Ph.D.
JHeimbach LLC March 26, 2012
923 Water Street
P.O. Box 66
Port Royal, VA 22535
Re: GRAS Notice No. GRN 000410
Dear Dr. Heimbach:
The Food and Drug Administration (FDA) is responding to the notice, dated November 7, 2011, that you submitted on behalf of Nestle Nutrition, U.S. (Nestle) in accordance with the agency's proposed regulation, proposed 21 CFR 170.36 (62 FR 18938; April 17, 1997; Substances Generally Recognized as Safe (GRAS); the GRAS proposal). FDA received the notice on November 14, 2011, filed it on November 16, 2011, and designated it as GRAS Notice No. GRN 000410.
The subject of the notice is Lactobacillus reuteri strain DSM 17938. The notice informs FDA of the view of Nestle that L. reuteri strain DSM 17938 is GRAS, through scientific procedures, for use as an ingredient in powdered whey-based term infant formula at a minimum level of 106 colony forming units per gram (cfu/g), but not higher than 108 cfu/g of powdered formula, produced in accordance with current good manufacturing practices (cGMPs).
As part of its notice, Nestle includes the report of a panel of individuals (Nestle's GRAS panel) who evaluated the data and information that are the basis for Nestle's GRAS determination. Nestle considers the members of its GRAS panel to be qualified by scientific training and experience to evaluate the safety of substances added to food. Nestle's GRAS panel discusses the identity, characterization, and production of the organism, intended use and exposure, as well as animal and human studies. Based on this review, and the totality of scientific evidence, Nestle's GRAS panel concluded that L. reuteri strain DSM 17938 is GRAS under the intended conditions of its use.
L. reuteri strain DSM 17938 was also the subject of GRN 000254 (filed on May 29, 2008)  for use in various foods that did not include infant formula; Nestle incorporates this notice by reference into GRN 000410. GRN 000254 describes L. reuteri strain DSM 17938 as a Gram-positive, non-spore forming, non-pathogenic lactic acid bacterium. Additionally, that notice contains extensive information regarding the identity, characterization, and production of L. reuteri strain DSM 17938, including the deletion of two antibiotic resistance plasmids (pLR581 and pLR585) from the parent L. reuteri strain ATCC 55730. Nestle briefly explains that, since the FDA's evaluation of GRN 000254, two studies describing the deletion of the plasmids from the parent strain have been published. The specifications for L. reuteri strain DSM 17938 are detailed in GRN 000254 (incorporated by reference into GRN 000410). For infant formula use, Nestle has an additional specification for absence (zero colony forming units) of Cronobacter sakazakii (formerly classified as Enterobacter sakazakii) in 10 grams of freeze-dried, powdered L. reuteri strain DSM 17938.
In GRN 000410, Nestle discusses experiments with L. reuteri strain DSM 17938 that assessed potential lactic acid production in reconstituted formulas held up to 6 hours at 4, 25, or 37 oC. Under these conditions, infant formulas prepared from powder containing 106 cfu L.reuteri strain DSM 17938 per gram were similar to controls and did not show increases in L- and D-lactic acid concentrations.
L. reuteri strain DSM 17938 is intended for use as an ingredient in powdered infant formula at a minimum level of 106 cfu/g. Nestle states that, in accordance with cGMPs, to achieve this minimum level in powdered infant formula, the addition level will be as high as 108 cfu/g. Nestle provides estimates of intake of L. reuteri strain DSM 17938 for term infants by assuming a concentration of 106 cfu/g in powdered formula. Using the typical dilution of powdered infant formula in water (13.5 g per 100 milliliters (mL)), the resultant concentration of L. reuteri strain DSM 17938 in prepared formula is 1.35 X 107 cfu/100 mL. Assuming an average consumption of 800 mL infant formula per day (d), the notifier estimates dietary exposure to be approximately 108 cfu/d of L. reuteri strain DSM 17938 for term infants. In a more detailed analysis, Nestle estimates 90th percentile intakes of formula (and corresponding intake of L. reuteri strain DSM 17938) based on published values of energy intakes for infants. Nestle notes that the highest energy intakes (on a body weight basis) are for 14-27 day-old boys, with intakes of 141.3 kilocalories per kilogram body weight per day (kcal/kg bw/d) at the 90th percentile. Using a typical energy density of 67.6 kcal/100 mL for term infant formula, Nestle estimates consumption of infant formula to be 209 mL formula per kg bw/d at the 90th percentile, corresponding to dietary exposure of 2.7 x 107 cfu/d L. reuteri strain DSM 17938.
In addition, Nestle notes that GRN 000254 included discussion of a number of published and unpublished studies in animals, human adults, children and infants, utilizing L. reuteri strain DSM 17938 as well as its parent strain, L. reuteri ATCC 55730, that support the current safety determination. Furthermore, Nestle discusses four additional clinical studies with term or pre-term infants fed L. reuteri strain DSM 17938 suspended in oil and given via oral drops or added to infant formula. Nestle notes these four studies, published since the completion of GRN 000254, show no adverse events attributable to feeding L. reuteri strain DSM 17938 and support the safety of the intended use of this ingredient in powdered term infant formula. Nestle reiterates that genomic analysis, previously discussed in GRN 000254, confirms that L. reuteri strain DSM 17938 does not harbor either virulence or transferable antibiotic resistance genes. Finally, Nestle provides published scientific data, as well as a discussion, refuting any safety issue related to possible metabolic acidosis from use of L. reuteri strain DSM 17938 in term infant formula.
Potential Labeling Issues
In describing data and information on clinical studies that Nestle relies on to conclude that L. reuteri strain DSM 17938 is GRAS under the conditions of its intended use, Nestle raises a potential issue under the labeling provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act). Under section 403(a) of the FD&C Act, a food is misbranded if its labeling is false or misleading in any particular. Section 403(r) of the FD&C Act lays out the statutory framework for the use of labeling claims that characterize the level of a nutrient in a food or that characterize the relationship of a nutrient to a disease or health-related condition. If products that contain L. reuteri strain DSM 17938 bear any claims on the label or in labeling, such claims are the purview of the Office of Nutrition, Labeling, and Dietary Supplements (ONLDS) in the Center for Food Safety and Applied Nutrition. The Office of Food Additive Safety neither consulted with ONLDS on this labeling issue nor evaluated the information in your notice to determine whether it would support any claims made about L. reuteri strain DSM 17938 on the label or in labeling.
Intended Use in Infant Formula
Under section 412 of the FD&C Act a manufacturer of a new infant formula must make a submission to FDA, providing required assurances about the formula, at least 90 days before the formula is marketed. Nestle should be aware that FDA's response to Nestle's GRAS notice does not alleviate the responsibility of any infant formula manufacturer who intends to market an infant formula that contains L. reuteri strain DSM 17938 to make the submission required by section 412.
Section 301(ll) of the FD&C Act
The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007, amends the FD&C Act to, among other things, add section 301(ll). Section 301(ll) of the FD&C Act prohibits the introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under section 505 of the FD&C Act, a biological product licensed under section 351 of the Public Health Service Act, or a drug or a biological product for which substantial clinical investigations have been instituted and their existence made public, unless one of the exemptions in section 301(ll)(1)-(4) applies. In its review of Nestle's notice that L. reuteri strain DSM 17938 is GRAS for the intended use, FDA did not consider whether section 301(ll) or any of its exemptions apply to foods containing L. reuteri strain DSM 17938. Accordingly, this response should not be construed to be a statement that foods that contain L. reuteri strain DSM 17938, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).
Based on the information provided by Nestle, as well as other information available to FDA, the agency has no questions at this time regarding Nestle's conclusion that L. reuteri strain DSM 17938 is GRAS under the intended conditions of use. The agency has not, however, made its own determination regarding the GRAS status of the subject use of L. reuteri strain DSM 17938. As always, it is the continuing responsibility of Nestle to ensure that food ingredients that the firm markets are safe, and are otherwise in compliance with all applicable legal and regulatory requirements.
In accordance with proposed 21 CFR 170.36(f), a copy of the text of this letter responding to GRN 000410, as well as a copy of the information in this notice that conforms to the information in the GRAS exemption claim (proposed 21 CFR 170.36(c)(1)), is available for public review and copying at www.fda.gov/grasnoticeinventory.
Dennis M. Keefe, Ph.D.
Office of Food Additive Safety
Center for Food Safety
and Applied Nutrition
 GRN 000254 was submitted by the manufacturer of oil suspensions of L.reuteri strain DSM 17938. These oil suspensions were used in published clinical studies cited in GRN 000410.